Ribonucleotide reductase subunit R2 regulates catalytic action of the enzyme to provide DNA
synthesis material via reduction. It has been continuously investigated as anticancer drug target for design
and discovery of its inhibitors. Present studies aim to design novel heterocyclic/aryl substituted and adamantyl
added thiosemicarbazones out fitted with improved cell permeability and effective RNR inhibition.
Design strategy renders significant use of virtual screening and molecular docking studies to converge search of selective
molecules for synthesis and further experimental studies. Selected candidates were synthesized and evaluated in vitro for
their RNR inhibitory activity (IC50, uM) on MCF-7 cells, breast cancer cell lines. Molecular docking results (docking
scores) and experimental results (IC50, uM) were found to be correlated and in agreement. Structure-based and ligandbased
studies of results substantiate regulative role of water molecules at catalytic site (H2O: 2057) as well as at RNR inhibitor
binding site (H2O: 2023, 2047, 2060 and 2070). Admantyl group has testified constant spatial position in docked
poses and involved in steric interactions with Cys271, Asp272, Phe237, Gly234 and Val238. Heterocyclic/aryl substitutions
equally offered H-bonds with water molecules (H2O: 2028, 2054, 2061 and 2073) along with amino acids Ser264,
Asp272, Tyr324 and Asn346. Present efforts to design new inhibitors incur new characteristics in RNR Inhibition.